1. Field of the Invention
The invention relates to the cardiovascular effects of cannabinoid compounds, i.e. naturally occurring as well as synthetic substances that bind with high affinity to cannabinoid receptors in the brain and in peripheral tissues of mammals, including man.
2. Description of the Prior Art
Naturally occurring cannabinoids may be divided into two categories, plant-derived and endogenous. Plant-derived cannabinoids are known to elicit dramatic psychobehavioral effects, exemplified by the well-known .DELTA..sup.9 -tetrahydrocannabinol (THC), the psychotropic principle in marijuana. They are also known to have complex cardiovascular effects, a prominent component of which is hypotension (Vollmer et al. J. Pharm. Pharmacol. 1974, 26:186-198) Endogenous cannabinoids (endocannabinoids) are a class of lipid-like molecules that share receptor binding sites with plant-derived cannabinoids and mimic many of their neurobehavioral effects (Mechoulam et al. Adv. Exp. Bio. Med. 1996, 402:95-101.) Two endocannabinoids have been characterized in some detail: arachidonyl ethanolamide (anandamide) (Devane et al. Science 1992, 258:1946-1949; Felder et al. Proc. Natl. Acad. Sci. USA. 1993, 90:7656-7660) and 2-arachidonyl glyceride (2-AG) (Mechoulam et al. Biochem. Pharmacol 1995, 50:83-90). Like plant-derived cannabinoids, both anandamine and 2-AG are capable of eliciting hypotension (Varga et al. FASEB J. 1998, 12:1035-1044; Varga et al. Eur. J. Pharmacol. 1995, 278:279-283; Stein et al. Br. J. Pharmacol. 1996, 119:107-114; Varga et al. Hypertension 1996, 28:682-688; Lake et al. Hypertension 1997, 29:1204-1210; Calignano et al. Eur. J. Pharmacol. 1997, 337: R1-R2). In addition, various cannabinoid compounds have been produced synthetically.
Cannabanoids exert their effects by binding to specific receptors located in the cell membrane. To date, two types of high-affinity cannabinoid receptors have been identified by molecular cloning: 1) CB1 receptors, present mostly in brain (Devane et al. Mol. Pharmacol. 1988, 34:605-613; Matsuda et al. Nature 1990, 346:561-564) but also in some peripheral tissues (Shire et al. J. Biol. Chem. 1995, 270:3726-3731; Ishac et al. Br. J. Pharmacol. 1996, 118:2023-2028), and 2) CB2 receptors, present on macrophages in the spleen (Munro et al. Nature 1993, 365:61-65).
The physiologic roles of endogenous cannabinoids and the pathways by which those roles are implemented are the subject of intense investigation. The observation that cannabinoids induce hypotension suggests a potential role for these substances in cardiovascular function. The results of a recent study by Lake et al.(J. Pharmacol. Exp. Ther. 1997, 281:1030-1037) lends credence to this idea. The study suggested that, when injected into anesthetized or conscious rats, anandamide and other cannabinoid substances cause profound hypotension mediated by peripheral CB1 receptors present in the heart and vasculature. However, further direct links between the endogenous cannabinoids and cardiovascular functions have been wanting. Results which are described herein supply that link and form the basis for the invention of a method described below whereby cannabinoid compounds can be used to ameliorate pathological conditions associated with hemodynamic abnormalities.